In plain terms

The claim being assessed: Misfolded tau and alpha-synuclein propagate cell to cell by templated conversion, driving progressive neurodegeneration.

Where the evidence stands: Γ — Plausible mechanism. There is a believable biological story and partial support, but the causal step has not been demonstrated.

What this mechanism does: This makes the process worse or keeps it going, but something else starts it.

Strongest evidence for it: The weakest-link conjunction returns Γ. Physiological host substrate can be recruited after imposed seeds, and source-restricted transfer and receptor perturbations demonstrate substantial capabilities. Selective blockade of spontaneous propagation has not established progression necessity in both disease families. Canonical PrP loss/rescue is stronger comparator evidence and is not transferred to the nominal tau/alpha-synuclein claim. Host state, compartment and intracellular toxicity constrain a universal spread-driven account.

What decisive evidence would look like

In plain terms, researchers would change the proposed cause, confirm it changed as intended, and measure a meaningful health outcome while checking other explanations. The result should be able to support or count against the claim.

Relative explanatory fit: Alternative ranked ahead

What this review means for Prion-like Spread of Misfolded Proteins

Claim being assessed: Misfolded tau and alpha-synuclein propagate cell to cell by templated conversion, driving progressive neurodegeneration.. This review asks whether the proposed factor causes the health outcome—not just whether the two appear together. For the wording assessed here, the evidence is rated Plausible mechanism (HSEF Γ; Moderate confidence). There is a believable biological story and partial support, but the causal step has not been demonstrated. That rating applies to this claim and scope; it does not mean the biological process is irrelevant in every setting.

Implications for health and treatment: This is an assessment of a causal explanation, not proof that a particular supplement, diet, test, or treatment improves health. A treatment claim needs studies that test the intervention in people and measure meaningful benefits and harms. These findings can help frame research and informed clinical questions, but they do not identify what is right for one person.

Limits for individual care: Evidence from cells, animals, associations, or a plausible mechanism may not predict what happens in people. The grade is limited to the exact claim, outcomes, and sources reviewed, and it is not a diagnosis or an individual forecast. Do not start, stop, or change care based on this page; discuss personal decisions with a qualified clinician.

Medical information notice: This review provides general health information, not medical advice. It cannot diagnose a condition or replace an individual discussion with a qualified clinician.

This assessment rests on 66 sources and 71 individually checked claims. 71 of those claims were verified against the original paper.

A low grade is not an accusation. It means the causal work has not been done yet, which is the ordinary state of most actively studied mechanisms in biology.

At a glance

Sub-claims assessed separately

ID	Sub-claim	Type	Level	Pivotal card
SC1	Misfolded tau and alpha-synuclein template conversion of homologous recipient protein.	mechanism	Γ	—
SC2	Endogenous pathological species spread between cells in disease-relevant circuits.	mechanism	Γ	Card ↗
SC3	Templated intercellular spread is a causal driver of progressive neuronal loss.	necessity	Γ	Card ↗
SC4	Prion-like mechanisms explain disease-class progression beyond forced inoculation.	generalization	Γ	Card ↗

Visual Evidence Cards · Pivotal Subclaims

Pivotal subclaim illustrations

Dark-theme simulated-micrograph renders and concise causal evidence summaries for the pivotal subclaims that govern this review's grade. Click any card to inspect the master 2400×2400 render.

Master 2400×2400 render ↗

Master 2400×2400 render ↗

Master 2400×2400 render ↗

Figures

Explanatory figures summarizing this review. They carry no evidential weight of their own; where a figure and the review differ, the review governs.

Full assessment

From here the review is written for a technical reader: caps and thresholds, competing models, the independence basis, and the citation ledger.

Sources: 66 primary reports; claims: 71; verified: 71; unverified: 0. Verification is bounded attribution. Access: 9 partial-body and 57 complete abstract/status examinations. Literature cutoff: 2026-10-06; source examination UTC date: 2026-10-06. No complete-paper audit or blinded calibration claimed. Adversarial review: Generated by Sol 6.1; adversarially reviewed by Claude Opus 5.5 (Anthropic) on 2026-10-06. 0 corrections applied (see ADVERSARIAL REVIEW AND APPROVAL). Status: Approved as revised.

AT A GLANCE

Tau and alpha-synuclein transfer and seed host protein in experiments; a selective natural propagation-to-neuronal-loss dependency is unresolved.

Deciding experiment: In independently generated spontaneous tau and alpha-synuclein disease systems with physiological donor/recipient substrate, interrupt a selective transfer or recipient-conversion step after onset and restore it with matched rescue.

Belief versus evidence: The weakest-link conjunction returns Γ. Physiological host substrate can be recruited after imposed seeds, and source-restricted transfer and receptor perturbations demonstrate substantial capabilities. Selective blockade of spontaneous propagation has not established progression necessity in both disease families. Canonical PrP loss/rescue is stronger comparator evidence and is not transferred to the nominal tau/alpha-synuclein claim. Host state, compartment and intracellular toxicity constrain a universal spread-driven account.

Best-supported rival: Selective vulnerability. Compare a transfer-only perturbation and matched rescue with substrate lowering, intrinsic-toxicity rescue and clearance controls in spontaneous disease. Measure lineage conversion separately from physical cargo and blinded neuronal survival. Compatible transfer and vulnerability mechanisms must be tested for mediation rather than treated as exclusive stories.

COMPETING MECHANISTIC MODELS

Rank 1: Selective vulnerability (Ε). Neuronal identity and intrinsic proteostasis condition aggregate susceptibility and injury. SNCA expression/ASO timing, PPN neuron phenotype, human neuronal subtype contrasts and tau synaptic-binding rescue support defined contexts. These findings can coexist with transfer and do not explain all disease origins.

Rank 2: Host-state determinism (Ε). Substrate amount, lysosomes and intracellular interactions determine pathogenic response. SNCA variants, host-null controls, GCase loops, TOM20 and intrinsic tau synaptic effects support specified dependencies. Mutation-associated disease or substrate suppression does not identify spread as the mediator.

Rank 3: Templated protein propagation (Γ). Transferred species recruit host protein and advance regional pathology. Wild-type host conversion, species-specific antibody, transport and route contrasts demonstrate experimental capability. Natural selective progression necessity remains unresolved; forced initiation and clinical engagement gaps limit generality.

Rank 4: Spread without toxicity (Γ). Cargo movement or seeded accumulation can occur without sustained neuronal injury. Tau-null transfer, increased seeding with metabolic recovery, protective microglial transfer and glial sharing separate these events. The positive PFF neuronal-loss cascade is real, so no universal harmlessness claim follows.

Rank 5: Glial vector propagation (Γ). Microglial vesicles and processing contribute to model spread. Exosome, TREM2/AEP and transfer experiments show a plausible vector route. Glia also clear cargo; forced loading, broad depletion and shared inflammatory effects do not establish native dominance.

The tournament does not alter the nominal level. Compatible pathways and flexible alternatives are not automatically proved by explaining observations.

FULL REVIEW

Registered claim and scope

Misfolded tau and alpha-synuclein propagate cell to cell by templated conversion, driving progressive neurodegeneration.

Use the index nominal tau-and-alpha-synuclein proposition. Unconditional decomposition overrides its stale unitary flag. Canonical PrP transmissibility is a comparator, not interchangeable evidence for ordinary sporadic tauopathy or synucleinopathy.

Selection: public-interest rank 24 from the editorial ranking compiled 2026-09-23; categorical prior verdicts were visible. Private fresh review; earlier documents are preserved.

Evidence and causal interpretation

Canonical PrP experiments establish host-homologous substrate dependence and post-invasion neuronal conversion dependence, with rescue of clinical and early functional abnormalities. Continued extraneuronal PrPSc is not sufficient for neuronal disease. These are comparators, not evidence that non-PrP proteins satisfy the same causal chain (PMID8100741, PMID14593181, PMID17270731).

SNCA familial mutation establishes protein relevance. Human graft inclusions supply a natural pathological spread lead, while donor-expression and microfluidic models directly show cargo transfer. Host origin, templating and neuronal loss remain separate, and transfer need not require a synapse (PMID9197268, PMID18391962, PMID19651612, PMID23109146, PMID24382629).

Wild-type PFF mice provide a strong imposed-seed cascade: original main text verifies ipsilateral neuronal loss, monomer/PBS and VTA/contralateral controls, SNCA-null protection and motor deficits. Gut PFF experiments add delayed TH/Nissl loss and vagal route interruption, but vagotomy also causes DMV ChAT loss and systemic gut changes. Neither is spontaneous disease or transfer-only rescue (PMID23161999, PMID31255487).

Physiological tau hosts can convert imposed seeds, and mouse-specific antibody narrows host recruitment. Source-restricted EC tau and spontaneous PS19 patterns support network capability but retain mutant sources. Tau-null transfer and host-dependent toxicity use distinct models; their results must not be collapsed into one selective spread-rescue experiment (PMID33005889, PMID39500576, PMID22365544, PMID22312444, PMID40886860, PMID26538322).

LAG3 positive receptor reports conflict with independently checked species-specific antibody, expression, survival and seeded-slice nulls. LRP1 and FAM171A2 offer other routes with their own pleiotropy. Receptor controversy weakens universality, not all propagation (PMID27708076, PMID38327094, PMID34309222, PMID36056345, PMID39977508).

Host phenotype and compartment matter: PPN connectome strength does not determine magnitude; human neuronal types differ despite comparable uptake. GCase feedback, TOM20 injury, substrate ASO timing and tau synaptic-binding rescue can contribute intrinsically. Native MSA filaments differ from recombinant structures; amplification products need not preserve all native conformations (PMID33177086, PMID40390134, PMID21700325, PMID27280685, PMID29502200, PMID33682798, PMID33472038, PMID32461689, PMID32025029).

Transfer/seeding is not automatically injurious. Human cortical-neuron PFF exposure produces early apoptosis followed by metabolic/caspase recovery while seeding increases; Arc loss reduces transfer with more early intracellular toxicity. Microglial nanotubes and increased glial sharing can relieve neuronal burden. HTRA1 remodeling lowers reporter seeding, but its MTT and later inclusion arms do not prove selective seeding mediation of survival (PMID40812158, PMID42372723, PMID39059388, PMID40993788, PMID38499535).

Human antibody outcomes constrain translation. SPARK and PASADENA primary outcomes are null; the PASADENA open-label external comparison is exploratory. PADOVA misses its primary endpoint despite HR0.84 and suggestive exploratory results; AMULET misses its predefined Bayesian threshold despite a 19 percent estimated slowing. UB-312 is a small safety/immunogenicity study; SPARK SAA persistence does not document complete seed blockade. TANGO fluid engagement is clinically null, while LAURIET has an isolated cognitive but no functional/global benefit (PMID35921450, PMID35921451, PMID39379705, PMID42208564, PMID42044642, PMID38902546, PMID38315945, PMID38012285, PMID37643887).

Consensus initially misapplied a 2026-only filter and used reviews/preprints. A corrected all-years targeted query returned Luk, Kim and Emmenegger indexed chunks; Kim route/host contrasts and Emmenegger nulls agree with direct original sections. Luk detailed controls and the 2025/2026 reports were missing from provider excerpts and were supplied by original-source retrieval. Provider omissions and coverage grids are not literature-absence evidence.

HYPOTHESIS STATE EVALUATION FRAMEWORK (HSEF v5.3)

Subclaim matrix and aggregation

Preregistered aggregation: weakest-link. The weakest-link conjunction returns Γ. Physiological host substrate can be recruited after imposed seeds, and source-restricted transfer and receptor perturbations demonstrate substantial capabilities. Selective blockade of spontaneous propagation has not established progression necessity in both disease families. Canonical PrP loss/rescue is stronger comparator evidence and is not transferred to the nominal tau/alpha-synuclein claim. Host state, compartment and intracellular toxicity constrain a universal spread-driven account. Sensitivities: weakest-link Γ; primary-subclaim Γ; scope-matched Γ.

Decisive-perturbation inventory and causal tally

[1] Gut PFF injection produces staged brain pathology, dopaminergic loss and motor deficits; vagotomy and SNCA absence prevent the cascade. Forced gut inoculation and global substrate removal do not identify spontaneous origin. Original Results verify TH plus Nissl stereology; vagotomy also removes 65 percent of DMV ChAT-positive cells and alters ghrelin, intake and gut function, so it is not a transfer-only block.

[2] Isogenic LRP1 loss reduces monomer/oligomer uptake more than PFF uptake; neuronal Lrp1 deletion reduces AAV-traced spread. LRP1 is pleiotropic; transferred AAV-expressed protein, templated conversion and neuron-loss mediation are distinct. No survival/function rescue is credited.

[4] PFFs recruit endogenous alpha-synuclein in primary neurons without overexpression and precede synaptic dysfunction and death. Exogenous entry and culture timing constrain physiological organismal spread necessity; correlated inclusion formation does not isolate the lethal intermediate.

[5] GCase loss impairs degradation and promotes aggregation toxicity; alpha-synuclein also inhibits GCase, producing a bidirectional loop. The self-propagating loop is intracellular proteostasis feedback, not proof of obligatory intercellular templating in sporadic PD.

[6] GBA1 patient-derived midbrain organoids form seeding-competent fibrils with dopaminergic loss and transmit pathology to control organoids; GCase-pathway drugs lower pathology. Organoid toxicity and genetic-risk background lack organismal follow-through; pathology lowering is not verified clinical rescue or selective spread mediation.

[7] Genetically affected and isogenic neurons show glucosylceramide-linked ectosome release; GCase inhibition increases vesicle traffic and alpha-synuclein pathology in mouse brains. Lipid and lysosomal changes affect donor production and recipient health; a major-route claim does not establish natural disease necessity or neuronal survival mediation.

[8] Neuronal LAG3 loss lowers tau PFF internalization, subsequent pathology and behavioral deficits. Imposed PFF initiation and receptor-expression controversy constrain scope; neuronal LAG3 and broad immune effects require independent confirmation. UpdateOf links a preprint.

[9] A pan-connexin blocker improves an induced oligodendroglial A53T MSA-C model while increasing oligomer sharing in glia and reducing neuronal burden. Sharing can protect in this defined compartment; broad connexin effects, induced overexpression and absent transfer-only rescue prevent universal conclusions. Oligomers rarely colocalize with p-alpha-synuclein.

[10] Worm HSP110 depletion lowers disaggregation, intercellular transmission and alpha-synuclein toxicity. Overall folding capacity is also impaired; a proteostasis-wide perturbation does not isolate transfer as the mediator or establish mammalian generality.

[12] Microglial nanotubes remove neuronal tau/alpha-synuclein aggregates and donate healthy mitochondria; mitochondrial inhibition removes neuroprotection. Protective exchange contrasts with transfer-as-injury, but culture rescue does not establish its dominance in native disease.

[14] Twenty-person UB-312 phase1 randomization establishes immunogenicity; CSF antibodies occur in 5 of 13 fully dosed recipients and seed reduction in a subset. Safety/antibody primary endpoints and exploratory seed effects do not demonstrate clinical benefit, selective spread blockade or an unbiased responding subgroup effect; clinical scales do not differ.

[17] HTRA1 and a protease-inactive mutant remodel PFFs and reduce reporter seeding; treated reaction products reduce primary-neuron p-alpha-synuclein and improve MTT signal. Original Results show mature-PFF reporter seeding decreases about 30–40 percent rather than absolute eradication. MTT at 24 hours precedes one-week inclusion assessment, so selective seeding mediation of survival is not proved; different formation/remodeling arms are kept separate.

[19] Modified alpha-synuclein binds TOM20 and impairs mitochondrial import; modest endogenous knockdown preserves import in an in-vivo model. Intrinsic mitochondrial toxicity does not require spread; postmortem concordance and import rescue do not establish complete human neuron-survival mediation.

[21] Microglial PFF-loaded exosomes seed neurons, drive injected mouse pathology/degeneration and are present in patient CSF; exosome inhibition or depletion lowers model transmission. Forced microglial cargo loading/injection, broad depletion, inflammation and autophagy effects do not isolate spontaneous spread-to-injury mediation.

[23] Isogenic control and SNCA-triplication human neurons show increasing seeding but recovery of mitochondrial function; early fibril exposure raises apoptosis without sustained late seeding toxicity. Original Results confirm early day1/3 caspase activation returns toward baseline by days14/21, no seeding-associated necrosis, and no 25-day respiration change from PFFs. Cultured cortical neurons, a particular fibril preparation and survival/adaptation cannot generalize to all seeds or nigral disease.

[25] TREM2-mediated microglial PFF uptake and AEP truncation enhance seeding; genetic loss or depletion impedes model pathology. Clearance, inflammatory and substrate-processing changes accompany spread reduction; no audited functional neuronal-loss rescue is credited from the abstract.

[26] LAG3 binding and loss experiments reduce PFF uptake and delay dopaminergic loss and behavioral deficits. PFF initiation and broad receptor/immune effects limit necessity inference; a later independent expression and survival-null study challenges universal neuronal-receptor attribution.

[27] PASADENA randomizes 316 patients; global MDS-UPDRS and DaT-SPECT endpoints do not show meaningful benefit. Motor-secondary signals do not reverse the primary conclusion; epitope occupancy or plasma binding does not verify blockade of the pathogenic interstitial species. Null is strategy-specific.

[29] AMULET treats 61 participants; estimated progression slowing is 19 percent but Bayesian probability 89.4 percent misses the prespecified 97.5 percent threshold. Primary endpoint is not met; an uncertain signal and acceptable safety justify further tests, not proof of propagation mediation. Full original body unavailable here.

[30] SPARK randomizes 357 patients; clinical and DaT-SPECT endpoints are null, and trial stops for futility. The tested extracellular antibody strategy fails; this does not demonstrate universal elimination of pathogenic seeds or refute all intracellular alpha-synuclein biology.

[32] Perampanel reduces neuronal PFF uptake and model pathology through activity-dependent macropinocytosis. AMPA activity affects physiology and multiple toxic processes; no clinical or audited neuron-survival rescue and no transfer-only intervention are established.

[34] Imaging tracks rapid PFF macropinocytosis to lysosomes and some transfer with exosome markers; inhibitors reduce uptake. Lysosomal uptake/transport does not demonstrate cytosolic recipient conversion, spontaneous spread or degeneration necessity.

[35] FAM171A2 binds fibrils selectively; neuronal knockdown and bemcentinib reduce uptake and model pathology/neurotoxicity. Risk-gene association and binding do not identify the full human mediator. Drug pleiotropy, model initiation and matched rescue details remain abstract-only.

[36] A single PFF injection into wild-type mice precedes connected pathology, ipsilateral dopamine-neuron loss and rotarod/wire-hang deficits; SNCA-null controls lack these lesions. Original main text confirms 15 and 35 percent ipsilateral loss at 90/180 days, with monomer/PBS, contralateral and VTA controls. Global substrate absence also removes intrinsic toxicity; imposed initiation does not prove natural spread necessity. Open-field activity and Y-maze are unchanged.

[37] SNCA ASOs prevent/reverse established PFF pathology and preserve dopaminergic function; human-target ASOs lower NHP CNS alpha-synuclein. Global synthesis lowering changes intrinsic substrate and toxicity, not selectively transfer; NHP distribution/CSF engagement is not demonstrated disease efficacy.

[38] Endogenous alpha-synuclein levels predict subtype susceptibility; early ASO or glutathione-related rescue protects PFF-vulnerable Math2 neurons. Late pathology reduction lacks comparable protection, revealing stage thresholds; substrate reduction and redox rescue are not transfer-only tests.

[39] Multiple antibody/transcript assays do not detect neuronal LAG3, and LAG3 loss has no A53T survival or seeded-slice pathology effect. Original Results verify species-specific antibody controls, activated-T-cell positive controls, human snRNAseq, small genotype survival groups and seeded wild-type/A53T slice nulls. A null proposed receptor does not eliminate alternative uptake routes or all propagation.

[40] SPARK biomarker reanalysis finds 93 percent baseline SAA positivity, persistence in 99 percent at week52 and no treatment or progression-linked biomarker effect. Same 357-person trial; no new randomization. Persistent SAA and absent biomarker effect weaken a claim that cinpanemab verified complete seed blockade.

[41] PADOVA randomizes 586 patients; motor-progression HR 0.84, 95 percent CI 0.69–1.01, p0.066 misses the primary endpoint. Exploratory clinical-activity signals merit follow-up but are not confirmatory efficacy. Actual pathogenic extracellular spread blockade is not demonstrated in this abstract; linked correction details remain unexamined.

[42] PrP-null mice resist scrapie whereas host-homologous transgenic reintroduction restores susceptibility. Canonical PrP substrate dependence is a comparator only; it cannot establish the same mechanism or natural transmission in tau/alpha-synuclein diseases.

[43] Post-invasion neuronal PrP depletion reverses spongiosis and prevents clinical disease despite accumulating extraneuronal PrPSc. Neuron-specific conversion dependence is stronger than aggregate presence; nonneuronal propagation can be nonpathogenic. Neither PrP result is interchangeable with tau or alpha-synuclein necessity.

[44] Neuronal PrP depletion rescues early cognition and electrophysiology before large deposits accumulate. Same conditional PrP platform as the earlier depletion study; functional rescue does not demonstrate non-PrP disease mechanisms.

[47] Neuron-derived alpha-synuclein enters neighboring cells and grafted precursors with inclusion/apoptosis markers; lysosomal failure increases accumulation. Transgenic source and apoptosis markers do not identify a physiological templated, transfer-specific degeneration dependency. Linked erratum has no PMID supplied and remains unresolved.

[49] Microglial depletion and exosome-synthesis inhibition reduced tau propagation in an AAV entorhinal-to-dentate model and changed dentate excitability. AAV expression and broad microglial/exosome effects do not isolate spontaneous tau templating as the mediator of neuron death. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

[50] Arc knockout nearly abolished intercellular transmission in mutant-tau mice while reducing EV tau and increasing intracellular accumulation with modest early toxicity. Transmission reduction did not yield uniform neuroprotection; developmental Arc functions and mutant transgenic expression complicate selective spread mediation. UpdateOf links the preceding version, not a separate replication. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

[51] LRP1 knockdown reduced tau uptake in human-derived cells and reduced neuronal tau spread in a mouse model. Receptor uptake is not identical to recipient conversion; LRP1 has broader trafficking functions and the abstract does not establish neuronal-loss prevention. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

[52] Cell-derived tau conformations retained strain-like characteristics across three inoculated transgenic-mouse generations and patient-derived biosensor isolates differed by tauopathy. Repeat-domain reporters and imposed serial inoculation establish templating capability, not natural human intercellular disease causation or infectivity equivalence to PrP. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

[53] Removing endogenous mouse tau preserved human-P301L transfer to recipient neurons but reduced neurotoxicity in a separate severe-tauopathy model despite similar tangle numbers. Donor-protein movement can occur without host templating, and tangle burden can dissociate from toxicity; human transgenes and tau-null physiology limit natural disease generalization. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

[54] A mouse-tau-specific antibody reduced human AD-tau-seeded pathology in female wild-type mice despite not binding the human inoculum. This narrows recipient-substrate involvement but still begins with imposed seeds; the abstract infers intraneuronal elongation and does not establish selective spread-mediated neuron survival. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

[55] Reducing Synaptogyrin-3 rescued mutant-tau synaptic plasticity, memory and synapse loss while neuroinflammation remained elevated. The contrast identifies synaptic toxicity independent of persistent glial activation; it does not directly test pathological species transfer. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

[57] LAURIET semorinemab improved ADAS-Cog11 decline at week 49 but not the coprimary activities-of-daily-living endpoint or global secondary measures. The prespecified coprimary trial result was negative; isolated cognitive benefit is credited without being relabeled overall efficacy or propagation-mediated neuroprotection. Original Results confirm a 2.89-point ADAS-Cog11 difference at week 49, with the largest post hoc item effect in word recognition. CSF tau fell but PET accumulation and atrophy rates did not differ. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

[58] Mutant-P301S brain extract induced filament assembly of wild-type human tau and regional pathology in inoculated transgenic recipients. The recipients express human tau and receive artificial intracerebral exposure; capability is not natural cell-to-cell necessity or neurodegeneration mediation. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

[59] Entorhinal-restricted P301L expression was followed by human tau in connected neurons lacking detectable transgene, coaggregation with mouse tau, synapse degeneration and EC loss. Low-level expression detection and source-cell deafferentation complicate inference; mutant overexpression does not isolate selective endogenous templating. Linked erratum details are unexamined. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

[60] Different human iPSC neuronal subtypes showed distinct susceptibility to identical tau or synuclein seeds; uptake/degradation did not explain the tau differences. This supports intrinsic vulnerability as a contributor to regional patterns; imposed aggregates and cultured neurons do not establish the full human progression mechanism. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

[61] Bassoon downregulation reduced tau seed-associated pathology and spread and rescued synaptic/behavioral defects and atrophy in experimental tauopathy systems. Bassoon regulates presynaptic function and seed stability as well as transport; matching source toxicity and selective recipient conversion remains essential to propagation mediation. Original Results show unchanged total human tau after preventive P0 Bassoon shRNA, and source GFP controls in the separate AAV transfer arm. These controls strengthen seed-mediated contribution but do not make presynaptic Bassoon a transfer-only intervention. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

[64] Human AD insoluble tau induced host-tau pathology in mice across Prnp genotypes; tau-null and species-specific antibody comparisons supported recipient tau origin, while PrP genotype did not change seeding/spread. Forced inoculation establishes host conversion capability and excludes an obligatory PrP receptor in this setting, not natural human tau propagation necessity. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

[66] Dextran-sulfate-assembled full-length tau induced host mouse-tau aggregation and connected-region pathology in nontransgenic mice after intracerebral injection. This removes a recipient overexpression requirement but retains artificial seed creation and forced entry; it is not observation of spontaneous human transmission. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Tally: 47 discriminating contrasts. Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines. Shared cohorts, experimental platforms, transgenic lineages and repeated outcomes do not constitute fully independent causal lines.

Cap audit, precedence and Β/Γ/Δ boundary

The neurodegeneration rubric credits disease-relevant mediator perturbation within its tested scope, but exogenous seeding alone remains capped for the natural disease inference. Wild-type recipients remove overexpression of the host substrate, not imposed initiation. LAG3/LRP1, vagotomy and ASO results are real perturbations but do not selectively isolate natural transfer-to-injury necessity in both protein families. PrP knockout/reintroduction and post-onset depletion support their own mechanism; no comparator grade is imported into tau/alpha-synuclein. The complete set is assessed for complementary errors, not re-capped simply because one component is weak.

Gamma hard-rule audit: Exogenous seeding alone cannot establish natural disease progression necessity. Physiological recipient expression does not make imposed initiation physiological. Protein transfer, host conversion and neuronal loss are three separate observations. Substrate depletion also changes intrinsic toxicity; PrP mechanisms are not inherited by non-PrP proteins.

SC1 cap: “Exogenous seeding models alone” Wild-type neuronal and animal recipients recruit host tau or alpha-synuclein, with species-specific antibody and SNCA-null controls. This is important physiological-substrate capability after forced entry. For the disease-relevant conversion mechanism, positive evidence remains dominated by imposed seeds or engineered sources, triggering the exogenous-seeding-alone ceiling; no claim is made that conversion never occurs.

SC1 field-valid definition: “ - Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo - Selective pathway inhibition that changes onset/progression while preserving broader viability - Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated” Positive full-scope result: no. Wild-type neuronal and animal recipients recruit host tau or alpha-synuclein, with species-specific antibody and SNCA-null controls. This is important physiological-substrate capability after forced entry. For the disease-relevant conversion mechanism, positive evidence remains dominated by imposed seeds or engineered sources, triggering the exogenous-seeding-alone ceiling; no claim is made that conversion never occurs.

SC2 field-valid definition: “ - Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo - Selective pathway inhibition that changes onset/progression while preserving broader viability - Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated” Positive full-scope result: no. Human graft pathology, donor-restricted animal protein and endogenous lipid/Arc perturbations strengthen physical transfer. Native molecular lineage in unforced disease remains incompletely distinguished from source overexpression, local generation and correlated vulnerability. PS19 spontaneous pathology retains widespread mutant expression.

SC3 field-valid definition: “ - Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo - Selective pathway inhibition that changes onset/progression while preserving broader viability - Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated” Positive full-scope result: no. Gut route interruption and receptor/source perturbations couple transmission to injury in models, but also alter substrate, immunity, physiology or initial insult. Arc, human-neuron seeding adaptation and protective glial sharing separate transfer from toxicity. Clinical strategies are null or mixed, without verified universal pathogenic seed blockade.

SC4 field-valid definition: “ - Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo - Selective pathway inhibition that changes onset/progression while preserving broader viability - Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated” Positive full-scope result: no. Tau/alpha-synuclein strains, native filament structures, recipient phenotypes and clinical responses vary. MSA transmission to sensitized A53T mice does not establish ordinary PD transmission or human contagiousness. SAA kinetics predict some cognitive outcomes but do not measure physical spread. Disease-class progression beyond imposed initiation remains Γ.

Upward threshold ladder

SC1 Δ: “Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.” Satisfied: no. Direct native donor–recipient lineage conversion at physiological expression, with substrate-selective loss and matched rescue, would extend imposed-seed capability to the registered disease mechanism.

SC2 Δ: “Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.” Satisfied: no. Trace spontaneously formed donor species into distinguished recipient protein in unforced disease, then selectively interrupt transfer without altering source burden or baseline viability.

SC3 Δ: “Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.” Satisfied: no. Post-onset transfer/conversion-specific suppression must alter neuron survival and function, with matched rescue restoring both spread and injury while intracellular toxicity is controlled.

SC4 Δ: “Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.” Satisfied: no. Replicate causal mediation across prospectively defined tauopathy and synucleinopathy subtypes, strains and stages, with human mechanism-sensitive clinical or genetic convergence.

Upper ladder: Familial SNCA evidence, human graft observations, clinical anti-tau/anti-alpha-synuclein trials and natural host-state contrasts were considered. They respectively establish protein relevance, natural pathological transfer leads or tested-strategy outcomes, not a common selective propagation mediator. Randomized efficacy is not an obligatory unique gate, but the assembled equivalents do not demonstrate broad natural progression necessity. Canonical PrP evidence has much stronger causal specificity within its own separate scope.

Independence: Sixty-six reports include three PrP comparators and 18 reused tau metadata records, including four reused original-body examinations from this same batch. These are not independent replications of the alpha-synuclein claim. SPARK biomarker and PASADENA extension reports are grouped with original trials; mutant-line, seeded platform and human cohort overlaps remain. Convergence narrows capability and alternatives but not the complete spontaneous mediator chain.

Physiological host/substrate contrasts [36, 66, 54]: Reduce donor signal and host-expression ambiguity while retaining imposed initiation.

Physical route and source restriction [1, 59, 48]: Reduce pure spatial covariance; vagotomy and forced sources retain distinct confounds.

Counterexamples separating transfer and toxicity [50, 23, 9]: Exclude automatic identity between spread reduction and neuroprotection.

Randomized clinical strategies [30, 27, 41, 29, 57]: Reduce treatment confounding; positive exploratory signals and endpoint failures are retained without assuming complete seed blockade.

Native structures and receptor challenge [20, 39]: Challenge recombinant strain fidelity and universal LAG3 dependence.

Falsification and pitfalls

Transfer and toxicity do not map one to one. Arc loss, human-neuron adaptation and protective glial sharing dissociate transfer/seeding from injury. Additional downgrade: False.

One proposed receptor is not universally required. LAG3 absence/expression controls and null survival/slice results challenge a broad neuronal LAG3 account. Additional downgrade: False.

Clinical strategy outcomes are not confirmed progression benefit. SPARK, PASADENA, PADOVA and AMULET miss primary endpoints; LAURIET has a real cognitive signal with negative functional/global outcomes. Additional downgrade: False.

PrP causality imported into non-PrP disease. Comparator knockout/depletion versus nominal tau/alpha-synuclein.

Protein cargo transfer equated with recipient templating. Grafts, axonal tracking and tau-null systems.

Primary clinical failure called complete seed-blockade falsification. Human CNS species/compartment engagement remains incomplete.

Provider year-filter or empty cells used as systematic gap proof. Initial Consensus incorrectly selected only 2026; its matrices contradict some extracted controls.

All disaggregation called harmless. HSP70/HSP110 can release toxic species; HTRA1 has distinct reaction arms and assays.

Adversarial steelman: above, then below

The strongest Δ/Ε case combines wild-type host conversion with gut/vagal interruption, receptor loss, source restriction and neuroprotection. The physiological host and original neuronal counts deserve full weight. Yet global substrate loss, vagotomy injury, receptor pleiotropy and imposed seed initiation leave natural propagation-specific mediation unisolated; tau Arc and clinical contrasts prevent assuming a shared universal driver.

The strongest Β case calls the literature only postmortem staging and metaphor. Direct axonal transfer, host-origin conversion, temporal neuronal-loss cascades and route perturbations exceed static association. Γ preserves these experimental capabilities without upgrading them to demonstrated broad endogenous necessity.

Reject Β for the actual mechanistic/temporal evidence and reject Δ for the unclosed full-scope selective mediator gate. Stronger PrP and narrowly defined substrate or vulnerability claims are acknowledged separately.

Final score, causal direction and M/S/D

The weakest-link conjunction returns Γ. Physiological host substrate can be recruited after imposed seeds, and source-restricted transfer and receptor perturbations demonstrate substantial capabilities. Selective blockade of spontaneous propagation has not established progression necessity in both disease families. Canonical PrP loss/rescue is stronger comparator evidence and is not transferred to the nominal tau/alpha-synuclein claim. Host state, compartment and intracellular toxicity constrain a universal spread-driven account.

Transfer and templating can amplify pathology in specified systems. Selective natural degeneration necessity and rate limitation across both families remain unresolved, so the broad role is conditional reinforcement. Clearance transfer may protect; physiological substrate recruitment after an imposed seed does not establish spontaneous initiation.

Momentum: Mechanistic only. Completed PADOVA/AMULET primary reports and recent ectosome, Arc and human-neuron experiments refine progression and host-state boundaries. Phase3 programs are mentioned by trial authors but fresh registry status is not independently checked here.

Stability: Stable. No verified pending study is asserted as an imminent score-changing result.

Divergence: Contested; no single implied-level arithmetic. These dimensions do not change level or confidence.

PROPOSED DECISIVE EXPERIMENTS

In independently generated spontaneous tau and alpha-synuclein disease systems with physiological donor/recipient substrate, interrupt a selective transfer or recipient-conversion step after onset and restore it with matched rescue.

Readout: Direct donor–recipient lineage, recipient conversion, regional pathology, blinded neuron survival and functional trajectory. Controls: Source protein load, host physiology, intracellular toxicity, clearance and peripheral/glial responses. Supporting: Verified selective suppression slows recipient conversion and subsequent neuron loss; matched rescue reinstates both in each prespecified system. Falsifying: Verified selective suppression leaves progression unchanged or increases intracellular injury despite less transfer.

RESEARCH TIMELINE

KNOWLEDGE GAPS

Identify native transmitted species and precursor–product conversion independently of uptake or pSer129 staining.

Test spontaneous donor–recipient transfer at physiological expression, without forced PFF entry or pan-neuronal mutant expression.

Develop selective post-onset transfer loss/rescue with matched source load, intracellular toxicity and clearance.

Resolve receptor expression and assay specificity independently across neuronal subtypes; retain LAG3 conflicting results.

Verify actual pathogenic species/compartment blockade in humans before interpreting negative clinical antibodies as propagation elimination.

Map strain, neuronal subtype, glial compartment and disease stage prospectively; transfer can be pathogenic, neutral or protective.

METHODS AND CONSENSUS CONTRIBUTION

Consensus was used through the signed-in browser for discovery, counterevidence, research-gap and timeline suggestions, and attempted checks of specific indexed full-text passages. Returned Methods/Results passages were reconciled with original-paper passages where available; failed retrievals, source substitutions and unverified aspects are recorded in the case reconciliation. Successful passage checks are distinguished from provider summaries. Provider screening counts, citation counts and meters were not used as primary counts or HSEF scores. This source log records access depth; it does not claim complete-paper or supplement review. The monthly API allowance was conserved: zero Consensus API calls in this batch.

REVIEWER NOTES

66 primary reports, including three explicitly tagged PrP comparators and 18 tau records reused from this same batch. Nine partial-body examinations: five new original alpha-synuclein sections and four reusable tau section audits. No full-paper or supplement audit; linked correction details remain qualified. Two Consensus Pro browser queries, zero Deep/API. Historical tau/neuro levels were already visible; this conjunction is not a blinded review.

Search leads, reviews, protocols and correction notices do not pad the primary count. Downloaded XML does not earn examination credit. Linked notices remain attached; unexamined correction details limit inference. This is a coordinator source/claim consistency assessment, not independent blinded calibration.

ADVERSARIAL REVIEW AND APPROVAL

Authoring model: Sol 6.1. Adversarial reviewer: Claude Opus 5.5 (Anthropic). Date: 2026-10-06.

Scope of checks. Reference PMIDs verified 66/66 against PubMed records (title, first author, year, journal); no retractions or expressions of concern found. Load-bearing claims spot-checked: 17, against the local examinations/ abstract set and the nine full-text/ and reused body-section receipts. Scoring logic re-derived: hard caps applied before thresholds; declared weakest-link aggregation applied as written over SC1-SC4; Β/Γ/Δ boundary and Δ threshold text compared verbatim with references/evidence-rubrics/01-neurodegeneration.md; independence basis not required below Ζ. Internal consistency checked across AT A GLANCE, the scorecard, the provenance header, the reference ledger, the decisive-perturbation tally, the research timeline and the evidence cards. Reference rendering was scanned for the collective-first-author builder bug.

Findings.

Checked and rejected (no change made).

1. Validator warning v5.claim_form (entry_form "phenomenon"). Rejected. The registered claim states propagation and its consequence ("propagate cell to cell by templated conversion, driving progressive neurodegeneration"), so the restatement grades a causal proposition rather than a topic. The warning is a form heuristic, not an error.
2. Timeline row "SPARK and PASADENA primary failures" cites one PMID. Rejected. The column is "Primary source" (singular); both trials are cited in full in the evidence section (PMID 35921450, PMID 35921451) and in REFERENCES. No factual error.
3. Whether the Kim gut/vagotomy experiment satisfies the rubric's "vagotomy-type natural experiment" Δ gate. Rejected as a level change. The rubric admits that route only "if confounding is rigorously controlled"; the examined Results show a 65 percent reduction in DMV ChAT-positive cells plus ghrelin, intake and gut-function changes after truncal vagotomy, which the review already cites as the disqualifier.
4. Whether SNCA-null protection constitutes "endogenous genetic deletion of the proposed mediator in vivo". Rejected as a level change. The nominated mediator is selective intercellular transfer and templated conversion; global substrate deletion also removes intrinsic (non-spread) toxicity, so it does not isolate the mediator.
5. Collective-first-author reference bug. Scanned all 66 reference entries; no instance of the leading-comma rendering. No change.
6. Citation-year convention. No print/e-pub year discrepancies beyond the accepted ±1 tolerance.
7. Iatrogenic amyloid-beta transmission literature. Checked for relevance; it lies outside the registered tau/alpha-synuclein scope and its absence is not a defect.

Claims verified against source (selection). Kordower 2008 fourteen-year graft Lewy-like inclusions; SPARK biomarker 93 percent (110/118) baseline seed positivity and 99 percent week-52 persistence in the same 357-participant trial; PASADENA 316 participants; PADOVA 586 randomised, hazard ratio 0.84 (95 percent CI 0.69-1.01, p=0.066); AMULET 61 treated, Bayesian probability 89.4 percent against a 97.5 percent threshold, 19 percent estimated slowing; UB-312 twenty patients randomised with CSF antibodies in 5/13 fully dosed; LAURIET 2.89-point ADAS-Cog11 difference at week 49 with negative coprimary function; TANGO 654 randomised; Luk 2012 original text 15 and 35 percent ipsilateral SNpc loss at 90 and 180 dpi with monomer/PBS, contralateral and VTA controls and unchanged open-field and Y-maze; Kim 2019 original text 65 percent DMV ChAT loss after truncal vagotomy with TH plus Nissl stereology; HTRA1 mature-PFF reporter seeding reduced about 30-40 percent with MTT at 24 hours preceding one-week inclusion assessment; Angelova 2025 original text day-1/3 caspase activation returning to control by days 14 and 21, no seeding-associated necrosis and no 25-day respiration change; Emmenegger 2021 original text cross-species anti-LAG3 antibody ELISA controls, activated T-lymphocyte positive controls, human snRNAseq, A53T survival groups (n=8, 9, 13, 8) and seeded-slice nulls.

Residual limitations. Access depth is unchanged: nine partial-body examinations and fifty-seven abstract/status examinations, with no complete-paper or supplement audit. Linked correction and erratum details for references 47 and 59 remain unexamined, as the review states. Verification of trial numbers rests on published abstracts and the selected Results paragraphs, not on protocols or supplementary appendices. This adversarial pass is not a blinded recalibration.

Approval: Following adversarial review and the corrections listed above, the revised document is approved. — Claude Opus 5.5 (Anthropic), 2026-10-06.

REFERENCES

1. Kim S, Kwon SH, Kam TI et al. Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease. Neuron. 2019. PMID 31255487. DOI: 10.1016/j.neuron.2019.05.035. Access: full_text_partial. Study: PMID31255487.

2. Chen K, Martens YA, Meneses A et al. LRP1 is a neuronal receptor for α-synuclein uptake and spread. Molecular neurodegeneration. 2022. PMID 36056345. DOI: 10.1186/s13024-022-00560-w. Access: abstract_metadata. Study: PMID36056345.

3. Horsager J, Andersen KB, Knudsen K et al. Brain-first versus body-first Parkinson's disease: a multimodal imaging case-control study. Brain : a journal of neurology. 2020. PMID 32830221. DOI: 10.1093/brain/awaa238. Access: abstract_metadata. Study: PMID32830221.

4. Volpicelli-Daley LA, Luk KC, Patel TP et al. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011. PMID 21982369. DOI: 10.1016/j.neuron.2011.08.033. Access: abstract_metadata. Study: PMID21982369.

5. Mazzulli JR, Xu YH, Sun Y et al. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011. PMID 21700325. DOI: 10.1016/j.cell.2011.06.001. Access: abstract_metadata. Study: PMID21700325.

6. Frattini E, Faustini G, Lopez G et al. Lewy pathology formation in patient-derived GBA1 Parkinson's disease midbrain organoids. Brain : a journal of neurology. 2025. PMID 39570889. DOI: 10.1093/brain/awae365. Access: abstract_metadata. Study: PMID39570889.

7. Jacquemyn J, Marriott B, Chang J et al. Glucosylceramide-induced ectosomes propagate pathogenic α-synuclein in Parkinson's disease. Nature cell biology. 2026. PMID 41680444. DOI: 10.1038/s41556-026-01871-6. Access: abstract_metadata. Study: PMID41680444.

8. Chen C, Kumbhar R, Wang H et al. Lymphocyte-Activation Gene 3 Facilitates Pathological Tau Neuron-to-Neuron Transmission. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2024. PMID 38327094. DOI: 10.1002/advs.202303775. Access: abstract_metadata. Study: PMID38327094.

9. Harada M, Masaki K, Tanaka T et al. Facilitated α-synuclein oligomer sharing among glial cells by a centrally acting connexin inhibitor attenuates a rapidly progressive multiple system atrophy-cerebellar type model by reducing the neuronal α-synuclein burden. Acta neuropathologica communications. 2025. PMID 40993788. DOI: 10.1186/s40478-025-02116-7. Access: abstract_metadata. Study: PMID40993788.

10. Tittelmeier J, Sandhof CA, Ries HM et al. The HSP110/HSP70 disaggregation system generates spreading-competent toxic α-synuclein species. The EMBO journal. 2020. PMID 32449565. DOI: 10.15252/embj.2019103954. Access: abstract_metadata. Study: PMID32449565.

11. Masuda-Suzukake M, Nonaka T, Hosokawa M et al. Pathological alpha-synuclein propagates through neural networks. Acta neuropathologica communications. 2014. PMID 25095794. DOI: 10.1186/s40478-014-0088-8. Access: abstract_metadata. Study: PMID25095794.

12. Scheiblich H, Eikens F, Wischhof L et al. Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes. Neuron. 2024. PMID 39059388. DOI: 10.1016/j.neuron.2024.06.029. Access: abstract_metadata. Study: PMID39059388.

13. Chakraborty R, Nonaka T, Hasegawa M et al. Tunnelling nanotubes between neuronal and microglial cells allow bi-directional transfer of α-Synuclein and mitochondria. Cell death & disease. 2023. PMID 37202391. DOI: 10.1038/s41419-023-05835-8. Access: abstract_metadata. Study: PMID37202391.

14. Eijsvogel P, Misra P, Concha-Marambio L et al. Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial. Nature medicine. 2024. PMID 38902546. DOI: 10.1038/s41591-024-03101-8. Access: abstract_metadata. Study: PMID38902546.

15. Mahul-Mellier AL, Burtscher J, Maharjan N et al. The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America. 2020. PMID 32075919. DOI: 10.1073/pnas.1913904117. Access: abstract_metadata. Study: PMID32075919.

16. Orrú CD, Vaughan DP, Vijiaratnam N et al. Diagnostic and prognostic value of α-synuclein seed amplification assay kinetic measures in Parkinson's disease: a longitudinal cohort study. The Lancet. Neurology. 2025. PMID 40541208. DOI: 10.1016/S1474-4422(25)00157-7. Access: abstract_metadata. Study: PMID40541208.

17. Chen S, Puri A, Bell B et al. HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species. Nature communications. 2024. PMID 38499535. DOI: 10.1038/s41467-024-46538-8. Access: full_text_partial. Study: PMID38499535.

18. Shahnawaz M, Mukherjee A, Pritzkow S et al. Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy. Nature. 2020. PMID 32025029. DOI: 10.1038/s41586-020-1984-7. Access: abstract_metadata. Study: PMID32025029.

19. Di Maio R, Barrett PJ, Hoffman EK et al. α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease. Science translational medicine. 2016. PMID 27280685. DOI: 10.1126/scitranslmed.aaf3634. Access: abstract_metadata. Study: PMID27280685.

20. Schweighauser M, Shi Y, Tarutani A et al. Structures of α-synuclein filaments from multiple system atrophy. Nature. 2020. PMID 32461689. DOI: 10.1038/s41586-020-2317-6. Access: abstract_metadata. Study: PMID32461689.

21. Guo M, Wang J, Zhao Y et al. Microglial exosomes facilitate α-synuclein transmission in Parkinson's disease. Brain : a journal of neurology. 2020. PMID 32355963. DOI: 10.1093/brain/awaa090. Access: abstract_metadata. Study: PMID32355963.

22. Prusiner SB, Woerman AL, Mordes DA et al. Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proceedings of the National Academy of Sciences of the United States of America. 2015. PMID 26324905. DOI: 10.1073/pnas.1514475112. Access: abstract_metadata. Study: PMID26324905.

23. Angelova PR, Esteras N, Evans J et al. α-synuclein fibrils per se but not α-synuclein seeded aggregation causes mitochondrial dysfunction and cell death in human neurons. Redox biology. 2025. PMID 40812158. DOI: 10.1016/j.redox.2025.103817. Access: full_text_partial. Study: PMID40812158.

24. Henrich MT, Geibl FF, Lakshminarasimhan H et al. Determinants of seeding and spreading of α-synuclein pathology in the brain. Science advances. 2020. PMID 33177086. DOI: 10.1126/sciadv.abc2487. Access: abstract_metadata. Study: PMID33177086.

25. Xiong M, Xia D, Yu H et al. Microglia Process α-Synuclein Fibrils and Enhance their Pathogenicity in a TREM2-Dependent Manner. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2025. PMID 39665233. DOI: 10.1002/advs.202413451. Access: abstract_metadata. Study: PMID39665233.

26. Mao X, Ou MT, Karuppagounder SS et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science (New York, N.Y.). 2016. PMID 27708076. DOI: 10.1126/science.aah3374. Access: abstract_metadata. Study: PMID27708076.

27. Pagano G, Taylor KI, Anzures-Cabrera J et al. Trial of Prasinezumab in Early-Stage Parkinson's Disease. The New England journal of medicine. 2022. PMID 35921451. DOI: 10.1056/NEJMoa2202867. Access: abstract_metadata. Study: PASADENA-randomization.

28. Pagano G, Monnet A, Reyes A et al. Sustained effect of prasinezumab on Parkinson's disease motor progression in the open-label extension of the PASADENA trial. Nature medicine. 2024. PMID 39379705. DOI: 10.1038/s41591-024-03270-6. Access: abstract_metadata. Study: PASADENA-randomization-extension.

29. Kjærsgaard L, Wiedemann J, Singer W et al. Safety and efficacy of the anti-α-synuclein monoclonal antibody amlenetug for the treatment of patients with multiple system atrophy (AMULET): a phase 2, randomised, double-blind, multicentre trial. The Lancet. Neurology. 2026. PMID 42044642. DOI: 10.1016/S1474-4422(26)00100-6. Access: abstract_metadata. Study: PMID42044642.

30. Lang AE, Siderowf AD, Macklin EA et al. Trial of Cinpanemab in Early Parkinson's Disease. The New England journal of medicine. 2022. PMID 35921450. DOI: 10.1056/NEJMoa2203395. Access: abstract_metadata. Study: SPARK-randomization.

31. Reyes JF, Rey NL, Bousset L et al. Alpha-synuclein transfers from neurons to oligodendrocytes. Glia. 2014. PMID 24382629. DOI: 10.1002/glia.22611. Access: abstract_metadata. Study: PMID24382629.

32. Ueda J, Uemura N, Sawamura M et al. Perampanel Inhibits α-Synuclein Transmission in Parkinson's Disease Models. Movement disorders : official journal of the Movement Disorder Society. 2021. PMID 33813737. DOI: 10.1002/mds.28558. Access: abstract_metadata. Study: PMID33813737.

33. Shimozawa A, Ono M, Takahara D et al. Propagation of pathological α-synuclein in marmoset brain. Acta neuropathologica communications. 2017. PMID 28148299. DOI: 10.1186/s40478-017-0413-0. Access: abstract_metadata. Study: PMID28148299.

34. Bayati A, Banks E, Han C et al. Rapid macropinocytic transfer of α-synuclein to lysosomes. Cell reports. 2022. PMID 35858558. DOI: 10.1016/j.celrep.2022.111102. Access: abstract_metadata. Study: PMID35858558.

35. Wu KM, Xu QH, Liu YQ et al. Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease. Science (New York, N.Y.). 2025. PMID 39977508. DOI: 10.1126/science.adp3645. Access: abstract_metadata. Study: PMID39977508.

36. Luk KC, Kehm V, Carroll J et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science (New York, N.Y.). 2012. PMID 23161999. DOI: 10.1126/science.1227157. Access: full_text_partial. Study: PMID23161999.

37. Cole TA, Zhao H, Collier TJ et al. α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson's disease. JCI insight. 2021. PMID 33682798. DOI: 10.1172/jci.insight.135633. Access: abstract_metadata. Study: PMID33682798.

38. Luna E, Decker SC, Riddle DM et al. Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity. Acta neuropathologica. 2018. PMID 29502200. DOI: 10.1007/s00401-018-1829-8. Access: abstract_metadata. Study: PMID29502200.

39. Emmenegger M, De Cecco E, Hruska-Plochan M et al. LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies. EMBO molecular medicine. 2021. PMID 34309222. DOI: 10.15252/emmm.202114745. Access: full_text_partial. Study: PMID34309222.

40. Hutchison RM, Fraser K, Yang M et al. Cinpanemab in Early Parkinson Disease: Evaluation of Biomarker Results From the Phase 2 SPARK Clinical Trial. Neurology. 2024. PMID 38315945. DOI: 10.1212/WNL.0000000000209137. Access: abstract_metadata. Study: SPARK-randomization.

41. Nikolcheva T, Pagano G, Anzures-Cabrera J et al. Efficacy and safety of intravenous prasinezumab in individuals with early-stage Parkinson's disease on stable symptomatic monotherapy (PADOVA): a phase 2b, multicentre, randomised, double-blind, placebo-controlled study. Lancet (London, England). 2026. PMID 42208564. DOI: 10.1016/S0140-6736(26)00865-2. Access: abstract_metadata. Study: PMID42208564.

42. Büeler H, Aguzzi A, Sailer A et al. Mice devoid of PrP are resistant to scrapie. Cell. 1993. PMID 8100741. DOI: 10.1016/0092-8674(93)90360-3. Access: abstract_metadata. Study: PMID8100741.

43. Mallucci G, Dickinson A, Linehan J et al. Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science (New York, N.Y.). 2003. PMID 14593181. DOI: 10.1126/science.1090187. Access: abstract_metadata. Study: conditional-neuronal-PrP-platform.

44. Mallucci GR, White MD, Farmer M et al. Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion-infected mice. Neuron. 2007. PMID 17270731. DOI: 10.1016/j.neuron.2007.01.005. Access: abstract_metadata. Study: conditional-neuronal-PrP-platform.

45. Polymeropoulos MH, Lavedan C, Leroy E et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science (New York, N.Y.). 1997. PMID 9197268. DOI: 10.1126/science.276.5321.2045. Access: abstract_metadata. Study: PMID9197268.

46. Kordower JH, Chu Y, Hauser RA et al. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nature medicine. 2008. PMID 18391962. DOI: 10.1038/nm1747. Access: abstract_metadata. Study: PMID18391962.

47. Desplats P, Lee HJ, Bae EJ et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proceedings of the National Academy of Sciences of the United States of America. 2009. PMID 19651612. DOI: 10.1073/pnas.0903691106. Access: abstract_metadata. Study: PMID19651612.

48. Freundt EC, Maynard N, Clancy EK et al. Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport. Annals of neurology. 2012. PMID 23109146. DOI: 10.1002/ana.23747. Access: abstract_metadata. Study: PMID23109146.

49. Asai H, Ikezu S, Tsunoda S et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nature neuroscience. 2015. PMID 26436904. DOI: 10.1038/nn.4132. Access: abstract_metadata. Study: PMID26436904.

50. Tyagi M, de Hoog E, Grega M et al. Arc mediates intercellular tau transmission via extracellular vesicles. Cell. 2026. PMID 42372723. DOI: 10.1016/j.cell.2026.06.008. Access: abstract_metadata. Study: PMID42372723.

51. Rauch JN, Luna G, Guzman E et al. LRP1 is a master regulator of tau uptake and spread. Nature. 2020. PMID 32296178. DOI: 10.1038/s41586-020-2156-5. Access: abstract_metadata. Study: PMID32296178.

52. Sanders DW, Kaufman SK, DeVos SL et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. 2014. PMID 24857020. DOI: 10.1016/j.neuron.2014.04.047. Access: abstract_metadata. Study: PMID24857020.

53. Wegmann S, Maury EA, Kirk MJ et al. Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity. The EMBO journal. 2015. PMID 26538322. DOI: 10.15252/embj.201592748. Access: abstract_metadata. Study: PMID26538322.

54. Jang E, Hoxha K, Mozier D et al. Targeting Endogenous Tau in Seeded Tauopathy Models Inhibits Tau Spread. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2024. PMID 39500576. DOI: 10.1523/JNEUROSCI.0877-24.2024. Access: abstract_metadata. Study: PMID39500576.

55. Largo-Barrientos P, Apóstolo N, Creemers E et al. Lowering Synaptogyrin-3 expression rescues Tau-induced memory defects and synaptic loss in the presence of microglial activation. Neuron. 2021. PMID 33472038. DOI: 10.1016/j.neuron.2020.12.016. Access: abstract_metadata. Study: PMID33472038.

56. Shulman M, Kong J, O'Gorman J et al. TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer's disease. Nature aging. 2023. PMID 38012285. DOI: 10.1038/s43587-023-00523-w. Access: full_text_partial. Study: PMID38012285.

57. Monteiro C, Toth B, Brunstein F et al. Randomized Phase II Study of the Safety and Efficacy of Semorinemab in Participants With Mild-to-Moderate Alzheimer Disease: Lauriet. Neurology. 2023. PMID 37643887. DOI: 10.1212/WNL.0000000000207663. Access: full_text_partial. Study: PMID37643887.

58. Clavaguera F, Bolmont T, Crowther RA et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nature cell biology. 2009. PMID 19503072. DOI: 10.1038/ncb1901. Access: abstract_metadata. Study: PMID19503072.

59. de Calignon A, Polydoro M, Suárez-Calvet M et al. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron. 2012. PMID 22365544. DOI: 10.1016/j.neuron.2011.11.033. Access: abstract_metadata. Study: PMID22365544.

60. Weidling I, Preiss CN, Chancellor SE et al. hiPSC-neurons recapitulate the subtype-specific cell intrinsic nature of susceptibility to neurodegenerative disease-relevant aggregation. Acta neuropathologica communications. 2025. PMID 40390134. DOI: 10.1186/s40478-025-02000-4. Access: abstract_metadata. Study: PMID40390134.

61. Martinez P, Patel H, You Y et al. Bassoon contributes to tau-seed propagation and neurotoxicity. Nature neuroscience. 2022. PMID 36344699. DOI: 10.1038/s41593-022-01191-6. Access: full_text_partial. Study: PMID36344699.

62. Ramirez DMO, Whitesell JD, Bhagwat N et al. Spontaneous pathology in PS19 tauopathy mice progresses via brain networks. Neurobiology of disease. 2025. PMID 40886860. DOI: 10.1016/j.nbd.2025.107072. Access: abstract_metadata. Study: PMID40886860.

63. Meisl G, Hidari E, Allinson K et al. In vivo rate-determining steps of tau seed accumulation in Alzheimer's disease. Science advances. 2021. PMID 34714685. DOI: 10.1126/sciadv.abh1448. Access: full_text_partial. Study: PMID34714685.

64. Sala-Jarque J, Gil V, Andrés-Benito P et al. The cellular prion protein does not affect tau seeding and spreading of sarkosyl-insoluble fractions from Alzheimer's disease. Scientific reports. 2024. PMID 39284839. DOI: 10.1038/s41598-024-72232-2. Access: abstract_metadata. Study: PMID39284839.

65. Liu L, Drouet V, Wu JW et al. Trans-synaptic spread of tau pathology in vivo. PloS one. 2012. PMID 22312444. DOI: 10.1371/journal.pone.0031302. Access: abstract_metadata. Study: PMID22312444.

66. Masuda-Suzukake M, Suzuki G, Hosokawa M et al. Dextran sulphate-induced tau assemblies cause endogenous tau aggregation and propagation in wild-type mice. Brain communications. 2020. PMID 33005889. DOI: 10.1093/braincomms/fcaa091. Access: abstract_metadata. Study: PMID33005889.

Source-specific evidence cards

[1] Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease.

Shows: Gut PFF injection produces staged brain pathology, dopaminergic loss and motor deficits; vagotomy and SNCA absence prevent the cascade.

Does not show: Forced gut inoculation and global substrate removal do not identify spontaneous origin. Original Results verify TH plus Nissl stereology; vagotomy also removes 65 percent of DMV ChAT-positive cells and alters ghrelin, intake and gut function, so it is not a transfer-only block.

Access/status: Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph1, 1:RESULTS:paragraph2, 1:RESULTS:paragraph3. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3, SC4.

[2] LRP1 is a neuronal receptor for α-synuclein uptake and spread.

Shows: Isogenic LRP1 loss reduces monomer/oligomer uptake more than PFF uptake; neuronal Lrp1 deletion reduces AAV-traced spread.

Does not show: LRP1 is pleiotropic; transferred AAV-expressed protein, templated conversion and neuron-loss mediation are distinct. No survival/function rescue is credited.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[3] Brain-first versus body-first Parkinson's disease: a multimodal imaging case-control study.

Shows: A 37-person de novo PD and 22-person iRBD imaging study shows patterns compatible with brain-first and body-first trajectories.

Does not show: Cross-sectional group ordering and denervation signals do not directly observe molecular transfer or establish either origin in an individual.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

[4] Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death.

Shows: PFFs recruit endogenous alpha-synuclein in primary neurons without overexpression and precede synaptic dysfunction and death.

Does not show: Exogenous entry and culture timing constrain physiological organismal spread necessity; correlated inclusion formation does not isolate the lethal intermediate.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[5] Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies.

Shows: GCase loss impairs degradation and promotes aggregation toxicity; alpha-synuclein also inhibits GCase, producing a bidirectional loop.

Does not show: The self-propagating loop is intracellular proteostasis feedback, not proof of obligatory intercellular templating in sporadic PD.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3, SC4.

[6] Lewy pathology formation in patient-derived GBA1 Parkinson's disease midbrain organoids.

Shows: GBA1 patient-derived midbrain organoids form seeding-competent fibrils with dopaminergic loss and transmit pathology to control organoids; GCase-pathway drugs lower pathology.

Does not show: Organoid toxicity and genetic-risk background lack organismal follow-through; pathology lowering is not verified clinical rescue or selective spread mediation.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[7] Glucosylceramide-induced ectosomes propagate pathogenic α-synuclein in Parkinson's disease.

Shows: Genetically affected and isogenic neurons show glucosylceramide-linked ectosome release; GCase inhibition increases vesicle traffic and alpha-synuclein pathology in mouse brains.

Does not show: Lipid and lysosomal changes affect donor production and recipient health; a major-route claim does not establish natural disease necessity or neuronal survival mediation.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

[8] Lymphocyte-Activation Gene 3 Facilitates Pathological Tau Neuron-to-Neuron Transmission.

Shows: Neuronal LAG3 loss lowers tau PFF internalization, subsequent pathology and behavioral deficits.

Does not show: Imposed PFF initiation and receptor-expression controversy constrain scope; neuronal LAG3 and broad immune effects require independent confirmation. UpdateOf links a preprint.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. UpdateOf: PMID37293032. Subclaims: SC2, SC3.

[9] Facilitated α-synuclein oligomer sharing among glial cells by a centrally acting connexin inhibitor attenuates a rapidly progressive multiple system atrophy-cerebellar type model by reducing the neuronal α-synuclein burden.

Shows: A pan-connexin blocker improves an induced oligodendroglial A53T MSA-C model while increasing oligomer sharing in glia and reducing neuronal burden.

Does not show: Sharing can protect in this defined compartment; broad connexin effects, induced overexpression and absent transfer-only rescue prevent universal conclusions. Oligomers rarely colocalize with p-alpha-synuclein.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[10] The HSP110/HSP70 disaggregation system generates spreading-competent toxic α-synuclein species.

Shows: Worm HSP110 depletion lowers disaggregation, intercellular transmission and alpha-synuclein toxicity.

Does not show: Overall folding capacity is also impaired; a proteostasis-wide perturbation does not isolate transfer as the mediator or establish mammalian generality.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[11] Pathological alpha-synuclein propagates through neural networks.

Shows: Three inoculation sites produce distinct connected-region pathology and recovered insoluble material reseeds wild-type brains.

Does not show: Imposed seeds, host pathology and serial transfer are capabilities; direct molecular lineage and natural neuronal-loss dependency remain unresolved.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[12] Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes.

Shows: Microglial nanotubes remove neuronal tau/alpha-synuclein aggregates and donate healthy mitochondria; mitochondrial inhibition removes neuroprotection.

Does not show: Protective exchange contrasts with transfer-as-injury, but culture rescue does not establish its dominance in native disease.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[13] Tunnelling nanotubes between neuronal and microglial cells allow bi-directional transfer of α-Synuclein and mitochondria.

Shows: Human neuronal–microglial nanotubes transfer alpha-synuclein predominantly to microglia and mitochondria to burdened neurons.

Does not show: Observed movement is not necessarily recipient templating; the protective interpretation lacks an organismal progression test.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[14] Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial.

Shows: Twenty-person UB-312 phase1 randomization establishes immunogenicity; CSF antibodies occur in 5 of 13 fully dosed recipients and seed reduction in a subset.

Does not show: Safety/antibody primary endpoints and exploratory seed effects do not demonstrate clinical benefit, selective spread blockade or an unbiased responding subgroup effect; clinical scales do not differ.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3, SC4.

[15] The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration.

Shows: A seeded neuronal model links later organelle-rich Lewy-body maturation to mitochondrial and synaptic dysfunction beyond early fibrillization.

Does not show: The integrated maturation process may mediate injury; culture correlations and forced seeding do not establish selective intercellular transfer necessity.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[16] Diagnostic and prognostic value of α-synuclein seed amplification assay kinetic measures in Parkinson's disease: a longitudinal cohort study.

Shows: Across 1631 participants, faster SAA kinetics predict cognitive decline in independent PD cohort analyses, including an AD-biomarker-negative subset.

Does not show: SAA is an in-vitro amplification readout, not physical spread rate; it does not establish motor/neuron-loss mediation. PPMI participants overlap other analyses.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC4.

[17] HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species.

Shows: HTRA1 and a protease-inactive mutant remodel PFFs and reduce reporter seeding; treated reaction products reduce primary-neuron p-alpha-synuclein and improve MTT signal.

Does not show: Original Results show mature-PFF reporter seeding decreases about 30–40 percent rather than absolute eradication. MTT at 24 hours precedes one-week inclusion assessment, so selective seeding mediation of survival is not proved; different formation/remodeling arms are kept separate.

Access/status: Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph17, 1:Results:paragraph26, 1:Results:paragraph28. No complete-paper or supplement audit claimed. UpdateOf: PMID37674720. Subclaims: SC1, SC3.

[18] Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy.

Shows: CSF PMCA products discriminate PD and MSA with distinct biochemical/biological properties.

Does not show: Amplification may select conformers; product identity and clinical diagnosis do not prove faithful in-vivo strain transfer or progressive neurotoxicity.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

[19] α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease.

Shows: Modified alpha-synuclein binds TOM20 and impairs mitochondrial import; modest endogenous knockdown preserves import in an in-vivo model.

Does not show: Intrinsic mitochondrial toxicity does not require spread; postmortem concordance and import rescue do not establish complete human neuron-survival mediation.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[20] Structures of α-synuclein filaments from multiple system atrophy.

Shows: Cryo-EM shows distinct native MSA filaments and differences from DLB and recombinant structures.

Does not show: Structure is not a transmission/necessity experiment. A linked correction exists; its details have not been examined, so fine structural claims are qualified.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID41125897. Subclaims: SC1, SC4.

[21] Microglial exosomes facilitate α-synuclein transmission in Parkinson's disease.

Shows: Microglial PFF-loaded exosomes seed neurons, drive injected mouse pathology/degeneration and are present in patient CSF; exosome inhibition or depletion lowers model transmission.

Does not show: Forced microglial cargo loading/injection, broad depletion, inflammation and autophagy effects do not isolate spontaneous spread-to-injury mediation.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[22] Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism.

Shows: Fourteen MSA brain extracts transmit disease to sensitized hemizygous A53T mice and reporter cells; six PD extracts do not in that assay.

Does not show: Host mutation and assay selectivity limit generalization; natural human transmissibility and common sporadic PD mechanisms are not established. Correction details remain unexamined.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID38830111. Subclaims: SC1, SC3, SC4.

[23] α-synuclein fibrils per se but not α-synuclein seeded aggregation causes mitochondrial dysfunction and cell death in human neurons.

Shows: Isogenic control and SNCA-triplication human neurons show increasing seeding but recovery of mitochondrial function; early fibril exposure raises apoptosis without sustained late seeding toxicity.

Does not show: Original Results confirm early day1/3 caspase activation returns toward baseline by days14/21, no seeding-associated necrosis, and no 25-day respiration change from PFFs. Cultured cortical neurons, a particular fibril preparation and survival/adaptation cannot generalize to all seeds or nigral disease.

Access/status: Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph2, 2:Results:paragraph9, 2:Results:paragraph12, 2:Results:paragraph22, 2:Results:paragraph25. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[24] Determinants of seeding and spreading of α-synuclein pathology in the brain.

Shows: PPN PFF pathology follows afferent connections but kinetics, magnitude and persistence are not proportional to connection strength; neuronal phenotype matters.

Does not show: Connectome restriction and cell-specific susceptibility coexist; imposed seeds do not identify unforced native transfer or natural onset.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

[25] Microglia Process α-Synuclein Fibrils and Enhance their Pathogenicity in a TREM2-Dependent Manner.

Shows: TREM2-mediated microglial PFF uptake and AEP truncation enhance seeding; genetic loss or depletion impedes model pathology.

Does not show: Clearance, inflammatory and substrate-processing changes accompany spread reduction; no audited functional neuronal-loss rescue is credited from the abstract.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[26] Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3.

Shows: LAG3 binding and loss experiments reduce PFF uptake and delay dopaminergic loss and behavioral deficits.

Does not show: PFF initiation and broad receptor/immune effects limit necessity inference; a later independent expression and survival-null study challenges universal neuronal-receptor attribution.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[27] Trial of Prasinezumab in Early-Stage Parkinson's Disease.

Shows: PASADENA randomizes 316 patients; global MDS-UPDRS and DaT-SPECT endpoints do not show meaningful benefit.

Does not show: Motor-secondary signals do not reverse the primary conclusion; epitope occupancy or plasma binding does not verify blockade of the pathogenic interstitial species. Null is strategy-specific.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3, SC4.

[28] Sustained effect of prasinezumab on Parkinson's disease motor progression in the open-label extension of the PASADENA trial.

Shows: PASADENA open-label extension has slower motor worsening than a PPMI external comparator over four years.

Does not show: This is exploratory nonrandomized follow-up of the same trial, with external-comparator and retention confounding; not an independent randomized efficacy replication.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3, SC4.

[29] Safety and efficacy of the anti-α-synuclein monoclonal antibody amlenetug for the treatment of patients with multiple system atrophy (AMULET): a phase 2, randomised, double-blind, multicentre trial.

Shows: AMULET treats 61 participants; estimated progression slowing is 19 percent but Bayesian probability 89.4 percent misses the prespecified 97.5 percent threshold.

Does not show: Primary endpoint is not met; an uncertain signal and acceptable safety justify further tests, not proof of propagation mediation. Full original body unavailable here.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3, SC4.

[30] Trial of Cinpanemab in Early Parkinson's Disease.

Shows: SPARK randomizes 357 patients; clinical and DaT-SPECT endpoints are null, and trial stops for futility.

Does not show: The tested extracellular antibody strategy fails; this does not demonstrate universal elimination of pathogenic seeds or refute all intracellular alpha-synuclein biology.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3, SC4.

[31] Alpha-synuclein transfers from neurons to oligodendrocytes.

Shows: Oligodendrocytes take up extracellular alpha-synuclein and grafted rat oligodendroglia contain host-neuronal AAV-expressed human protein.

Does not show: Transfer of donor protein is not obligatory endogenous recipient conversion; forced source expression and graft environment limit native MSA interpretation.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[32] Perampanel Inhibits α-Synuclein Transmission in Parkinson's Disease Models.

Shows: Perampanel reduces neuronal PFF uptake and model pathology through activity-dependent macropinocytosis.

Does not show: AMPA activity affects physiology and multiple toxic processes; no clinical or audited neuron-survival rescue and no transfer-only intervention are established.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[33] Propagation of pathological α-synuclein in marmoset brain.

Shows: Inoculated wild-type marmosets develop connected-region Lewy-like inclusions and fewer ipsilateral TH-positive neurons at three months.

Does not show: Forced seeds remain; TH-positive counts alone may reflect marker loss without additional stereological identity checks; no full neuronal-loss/function audit was available.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[34] Rapid macropinocytic transfer of α-synuclein to lysosomes.

Shows: Imaging tracks rapid PFF macropinocytosis to lysosomes and some transfer with exosome markers; inhibitors reduce uptake.

Does not show: Lysosomal uptake/transport does not demonstrate cytosolic recipient conversion, spontaneous spread or degeneration necessity.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[35] Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease.

Shows: FAM171A2 binds fibrils selectively; neuronal knockdown and bemcentinib reduce uptake and model pathology/neurotoxicity.

Does not show: Risk-gene association and binding do not identify the full human mediator. Drug pleiotropy, model initiation and matched rescue details remain abstract-only.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[36] Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice.

Shows: A single PFF injection into wild-type mice precedes connected pathology, ipsilateral dopamine-neuron loss and rotarod/wire-hang deficits; SNCA-null controls lack these lesions.

Does not show: Original main text confirms 15 and 35 percent ipsilateral loss at 90/180 days, with monomer/PBS, contralateral and VTA controls. Global substrate absence also removes intrinsic toxicity; imposed initiation does not prove natural spread necessity. Open-field activity and Y-maze are unchanged.

Access/status: Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Main text:paragraph2, 1:Main text:paragraph3, 1:Main text:paragraph6, 1:Main text:paragraph8. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[37] α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson's disease.

Shows: SNCA ASOs prevent/reverse established PFF pathology and preserve dopaminergic function; human-target ASOs lower NHP CNS alpha-synuclein.

Does not show: Global synthesis lowering changes intrinsic substrate and toxicity, not selectively transfer; NHP distribution/CSF engagement is not demonstrated disease efficacy.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[38] Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity.

Shows: Endogenous alpha-synuclein levels predict subtype susceptibility; early ASO or glutathione-related rescue protects PFF-vulnerable Math2 neurons.

Does not show: Late pathology reduction lacks comparable protection, revealing stage thresholds; substrate reduction and redox rescue are not transfer-only tests.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[39] LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies.

Shows: Multiple antibody/transcript assays do not detect neuronal LAG3, and LAG3 loss has no A53T survival or seeded-slice pathology effect.

Does not show: Original Results verify species-specific antibody controls, activated-T-cell positive controls, human snRNAseq, small genotype survival groups and seeded wild-type/A53T slice nulls. A null proposed receptor does not eliminate alternative uptake routes or all propagation.

Access/status: Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph12, 1:Results:paragraph20, 1:Results:paragraph60, 1:Results:paragraph67. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[40] Cinpanemab in Early Parkinson Disease: Evaluation of Biomarker Results From the Phase 2 SPARK Clinical Trial.

Shows: SPARK biomarker reanalysis finds 93 percent baseline SAA positivity, persistence in 99 percent at week52 and no treatment or progression-linked biomarker effect.

Does not show: Same 357-person trial; no new randomization. Persistent SAA and absent biomarker effect weaken a claim that cinpanemab verified complete seed blockade.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3, SC4.

[41] Efficacy and safety of intravenous prasinezumab in individuals with early-stage Parkinson's disease on stable symptomatic monotherapy (PADOVA): a phase 2b, multicentre, randomised, double-blind, placebo-controlled study.

Shows: PADOVA randomizes 586 patients; motor-progression HR 0.84, 95 percent CI 0.69–1.01, p0.066 misses the primary endpoint.

Does not show: Exploratory clinical-activity signals merit follow-up but are not confirmatory efficacy. Actual pathogenic extracellular spread blockade is not demonstrated in this abstract; linked correction details remain unexamined.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID42392102. Subclaims: SC3, SC4.

[42] Mice devoid of PrP are resistant to scrapie.

Shows: PrP-null mice resist scrapie whereas host-homologous transgenic reintroduction restores susceptibility.

Does not show: Canonical PrP substrate dependence is a comparator only; it cannot establish the same mechanism or natural transmission in tau/alpha-synuclein diseases.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[43] Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis.

Shows: Post-invasion neuronal PrP depletion reverses spongiosis and prevents clinical disease despite accumulating extraneuronal PrPSc.

Does not show: Neuron-specific conversion dependence is stronger than aggregate presence; nonneuronal propagation can be nonpathogenic. Neither PrP result is interchangeable with tau or alpha-synuclein necessity.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[44] Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion-infected mice.

Shows: Neuronal PrP depletion rescues early cognition and electrophysiology before large deposits accumulate.

Does not show: Same conditional PrP platform as the earlier depletion study; functional rescue does not demonstrate non-PrP disease mechanisms.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[45] Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.

Shows: A segregating SNCA mutation occurs in an Italian kindred and three unrelated Greek families with dominant PD.

Does not show: Inherited gene causality supports protein relevance, not selective propagation mediation or direct generalization to sporadic disease.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC4.

[46] Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease.

Shows: Fourteen-year-old human nigral grafts have Lewy-like alpha-synuclein/ubiquitin inclusions and reduced DAT staining.

Does not show: A natural host-to-graft lead, but graft stress, shared milieu and de-novo aggregation remain alternatives; donor–recipient protein lineage and lethal templating were not directly measured.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

[47] Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein.

Shows: Neuron-derived alpha-synuclein enters neighboring cells and grafted precursors with inclusion/apoptosis markers; lysosomal failure increases accumulation.

Does not show: Transgenic source and apoptosis markers do not identify a physiological templated, transfer-specific degeneration dependency. Linked erratum has no PMID supplied and remains unresolved.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMIDnot supplied. Subclaims: SC2, SC3.

[48] Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport.

Shows: Microfluidic imaging tracks fibrils along axons into second-order neurons; transfer does not appear to require synapses.

Does not show: Physical cargo transfer under imposed exposure is not recipient endogenous conversion or organismal neuron-loss mediation.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[49] Depletion of microglia and inhibition of exosome synthesis halt tau propagation.

Shows: Microglial depletion and exosome-synthesis inhibition reduced tau propagation in an AAV entorhinal-to-dentate model and changed dentate excitability.

Does not show: AAV expression and broad microglial/exosome effects do not isolate spontaneous tau templating as the mediator of neuron death. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[50] Arc mediates intercellular tau transmission via extracellular vesicles.

Shows: Arc knockout nearly abolished intercellular transmission in mutant-tau mice while reducing EV tau and increasing intracellular accumulation with modest early toxicity.

Does not show: Transmission reduction did not yield uniform neuroprotection; developmental Arc functions and mutant transgenic expression complicate selective spread mediation. UpdateOf links the preceding version, not a separate replication. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. UpdateOf: PMID39484489. Subclaims: SC2, SC3.

[51] LRP1 is a master regulator of tau uptake and spread.

Shows: LRP1 knockdown reduced tau uptake in human-derived cells and reduced neuronal tau spread in a mouse model.

Does not show: Receptor uptake is not identical to recipient conversion; LRP1 has broader trafficking functions and the abstract does not establish neuronal-loss prevention. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[52] Distinct tau prion strains propagate in cells and mice and define different tauopathies.

Shows: Cell-derived tau conformations retained strain-like characteristics across three inoculated transgenic-mouse generations and patient-derived biosensor isolates differed by tauopathy.

Does not show: Repeat-domain reporters and imposed serial inoculation establish templating capability, not natural human intercellular disease causation or infectivity equivalence to PrP. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[53] Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity.

Shows: Removing endogenous mouse tau preserved human-P301L transfer to recipient neurons but reduced neurotoxicity in a separate severe-tauopathy model despite similar tangle numbers.

Does not show: Donor-protein movement can occur without host templating, and tangle burden can dissociate from toxicity; human transgenes and tau-null physiology limit natural disease generalization. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC1, SC3.

[54] Targeting Endogenous Tau in Seeded Tauopathy Models Inhibits Tau Spread.

Shows: A mouse-tau-specific antibody reduced human AD-tau-seeded pathology in female wild-type mice despite not binding the human inoculum.

Does not show: This narrows recipient-substrate involvement but still begins with imposed seeds; the abstract infers intraneuronal elongation and does not establish selective spread-mediated neuron survival. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[55] Lowering Synaptogyrin-3 expression rescues Tau-induced memory defects and synaptic loss in the presence of microglial activation.

Shows: Reducing Synaptogyrin-3 rescued mutant-tau synaptic plasticity, memory and synapse loss while neuroinflammation remained elevated.

Does not show: The contrast identifies synaptic toxicity independent of persistent glial activation; it does not directly test pathological species transfer. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[56] TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer's disease.

Shows: TANGO randomized 654 early-AD participants and showed no favorable cognitive/functional CDR-SB change with gosuranemab despite reduced unbound N-terminal CSF tau.

Does not show: Safety was primary and clinical efficacy secondary; drug engagement of a soluble N-terminal pool does not demonstrate selective blockade of all tau propagation. Original Results confirm 80.1–92.6 percent unbound N-terminal CSF tau reduction, no tau-PET dose response and no favorable atrophy response. An isolated exploratory cognitive result was worse, without a dose response; it is not treated as a definitive toxicity test. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph19, 1:Results:paragraph23, 1:Results:paragraph28, 1:Results:paragraph33, 1:Results:paragraph38. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[57] Randomized Phase II Study of the Safety and Efficacy of Semorinemab in Participants With Mild-to-Moderate Alzheimer Disease: Lauriet.

Shows: LAURIET semorinemab improved ADAS-Cog11 decline at week 49 but not the coprimary activities-of-daily-living endpoint or global secondary measures.

Does not show: The prespecified coprimary trial result was negative; isolated cognitive benefit is credited without being relabeled overall efficacy or propagation-mediated neuroprotection. Original Results confirm a 2.89-point ADAS-Cog11 difference at week 49, with the largest post hoc item effect in word recognition. CSF tau fell but PET accumulation and atrophy rates did not differ. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph8, 2:Results:paragraph15, 2:Results:paragraph17, 2:Results:paragraph19, 2:Results:paragraph20. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[58] Transmission and spreading of tauopathy in transgenic mouse brain.

Shows: Mutant-P301S brain extract induced filament assembly of wild-type human tau and regional pathology in inoculated transgenic recipients.

Does not show: The recipients express human tau and receive artificial intracerebral exposure; capability is not natural cell-to-cell necessity or neurodegeneration mediation. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[59] Propagation of tau pathology in a model of early Alzheimer's disease.

Shows: Entorhinal-restricted P301L expression was followed by human tau in connected neurons lacking detectable transgene, coaggregation with mouse tau, synapse degeneration and EC loss.

Does not show: Low-level expression detection and source-cell deafferentation complicate inference; mutant overexpression does not isolate selective endogenous templating. Linked erratum details are unexamined. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMIDnot supplied. Subclaims: SC2, SC1, SC3.

[60] hiPSC-neurons recapitulate the subtype-specific cell intrinsic nature of susceptibility to neurodegenerative disease-relevant aggregation.

Shows: Different human iPSC neuronal subtypes showed distinct susceptibility to identical tau or synuclein seeds; uptake/degradation did not explain the tau differences.

Does not show: This supports intrinsic vulnerability as a contributor to regional patterns; imposed aggregates and cultured neurons do not establish the full human progression mechanism. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC1.

[61] Bassoon contributes to tau-seed propagation and neurotoxicity.

Shows: Bassoon downregulation reduced tau seed-associated pathology and spread and rescued synaptic/behavioral defects and atrophy in experimental tauopathy systems.

Does not show: Bassoon regulates presynaptic function and seed stability as well as transport; matching source toxicity and selective recipient conversion remains essential to propagation mediation. Original Results show unchanged total human tau after preventive P0 Bassoon shRNA, and source GFP controls in the separate AAV transfer arm. These controls strengthen seed-mediated contribution but do not make presynaptic Bassoon a transfer-only intervention. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph21, 1:Results:paragraph26, 1:Results:paragraph33, 1:Results:paragraph36, 1:Results:paragraph44. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC1, SC3.

[62] Spontaneous pathology in PS19 tauopathy mice progresses via brain networks.

Shows: Whole-brain age-series maps of pan-neuronal P301S PS19 mice fitted retrograde-biased connectivity models without injected seeds.

Does not show: Spontaneous pathology is valuable but still occurs with widespread mutant human tau expression; modeled phospho-tau progression is not directly traced protein transfer or selective spread blockade. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. UpdateOf: PMID37293074. Subclaims: SC2.

[63] In vivo rate-determining steps of tau seed accumulation in Alzheimer's disease.

Shows: Kinetic fits across multiple human seed/tau measures suggested local replication, rather than interregional spread, limits neocortical accumulation from Braak III onward.

Does not show: The inferred approximately five-year seed doubling is model-dependent and stage-specific; it does not show early seeding is irrelevant or experimentally identify a clinical rate-limiting mediator. Original Results explicitly subsume local cell-to-cell transfer into the replication term. The contrast concerns interregional spread, not all transfer; extrapolation before Braak III is untested. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph3, 1:RESULTS:paragraph4, 1:RESULTS:paragraph5, 1:RESULTS:paragraph13, 1:RESULTS:paragraph14, 1:RESULTS:paragraph15, 1:RESULTS:paragraph16, 1:RESULTS:paragraph17. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[64] The cellular prion protein does not affect tau seeding and spreading of sarkosyl-insoluble fractions from Alzheimer's disease.

Shows: Human AD insoluble tau induced host-tau pathology in mice across Prnp genotypes; tau-null and species-specific antibody comparisons supported recipient tau origin, while PrP genotype did not change seeding/spread.

Does not show: Forced inoculation establishes host conversion capability and excludes an obligatory PrP receptor in this setting, not natural human tau propagation necessity. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[65] Trans-synaptic spread of tau pathology in vivo.

Shows: Entorhinal-biased human-tau transgenic mice developed human tau staining and mature pathology in connected hippocampal and cortical regions with age.

Does not show: Distribution and expression restriction support transfer but do not directly visualize a precursor-product lineage or separate low-level transgene expression from recipient conversion. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[66] Dextran sulphate-induced tau assemblies cause endogenous tau aggregation and propagation in wild-type mice.

Shows: Dextran-sulfate-assembled full-length tau induced host mouse-tau aggregation and connected-region pathology in nontransgenic mice after intracerebral injection.

Does not show: This removes a recipient overexpression requirement but retains artificial seed creation and forced entry; it is not observation of spontaneous human transmission. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC1.

Documentary record

Every grade on this site is reproducible from its record. The files below are the posted edition exactly as assessed.

• SHA256.txt
• codex-correction-provenance.json
• consensus-addendum.md
• consensus-validation.json
• edition-approval-audit.json
• prion-like-protein-spread.review.md
• prion-like-protein-spread.scorecard.json
• validation-report.json
• validation-round2-2026-10-14.json
• validation.txt

Sources: 66 · load-bearing claims: 71 · verified: 71 · unverified: 0 · contradicted: 0 · schema 5.3